This invention relates to compounds which are agonists of the progesterone receptor, their preparation and utility.
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
Jones, et al, described in U.S. Pat. No. 5,688,810 the PR antagonist dihydroquinoline A. 
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995). 
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). Kuhla, et al, taught the oxindole M as a cardiotonic (WO 86/03749). Weber, described the oxindole N for cardiovascular indications (WO 91/06545). Fischer, et al, claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516). R=variousSingh, et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248, 1994). Andreani, et al, described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407, 1990). Binder, et al, described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767). Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. Nos. 4,440,785, 4,670,566). Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545). Bohm, et al, include the generic structure U (WO 91/04974). JP 63112584 A contains the generic structure V: Boar, et al, described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1). Kende, et al, described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982). 